Activation states of blood eosinophils in asthma

Abstract

Asthma is characterized by airway inflammation rich in eosinophils. Airway eosinophilia is associated with exacerbations and has been suggested to play a role in airway remodelling. Recruitment of eosinophils from the circulation requires that blood eosinophils become activated, leading to their arrest on the endothelium and extravasation. Circulating eosinophils can be envisioned as potentially being in different activation states, including non-activated, pre-activated or 'primed', or fully activated. In addition, the circulation can potentially be deficient of pre-activated or activated eosinophils, because such cells have marginated on activated endothelium or extravasated into the tissue. A number of eosinophil surface proteins, including CD69, L-selectin, intercellular adhesion molecule-1 (ICAM-1, CD54), CD44, P-selectin glycoprotein ligand-1 (PSGL-1, CD162), cytokine receptors, Fc receptors, integrins including αM integrin (CD11b), and activated conformations of Fc receptors and integrins, have been proposed to report cell activation. Variation in eosinophil activation states may be associated with asthma activity. Eosinophil surface proteins proposed to be activation markers, with a particular focus on integrins, and evidence for associations between activation states of blood eosinophils and features of asthma are reviewed here. Partial activation of β1 and β2 integrins on blood eosinophils, reported by monoclonal antibodies (mAbs) N29 and KIM-127, is associated with impaired pulmonary function and airway eosinophilia, respectively, in non-severe asthma. The association with lung function does not occur in severe asthma, presumably due to greater eosinophil extravasation, specifically of activated or pre-activated cells, in severe disease.

Fig. 1. Model of activation states of eosinophils in circulation and during arrest and extravasation in asthma

1. Circulating non-activated eosinophil with α₄β₁ and α_Mβ₂ in the inactive integrin conformation, as found in normal subjects, some subjects with non-severe asthma, or in severe asthma; sampled in severe asthma due to great extravasation of activated cells.

2. Pre-activated or “primed” circulating eosinophil with (variable numbers of) α₄β₁ and α_Mβ₂ in the intermediate-activity integrin conformation, as a result of P-selectin- and IL-5-triggered signaling, respectively, as found to varying degree primarily in some subjects with non-severe asthma (in vivo it is most likely P-selectin on the surface of activated platelets that is responsible for this activation of α₄β₁).

3. Eosinophil arresting on activated endothelium in asthma with α₄β₁ and α_Mβ₂ in unknown state, likely in the intermediate-activity integrin conformation, with α₄β₁ primarily mediating arrest on VCAM-1 with a possible minor contribution of α_Mβ₂.

4. Extravasated or tissue eosinophil in asthma with α₄β₁ and α_Mβ₂ in the high-activity integrin conformation (and with down-regulated IL-5 receptor), and α_Mβ₂ interacting with periostin in the extracellular matrix.

Please see text for references. ECM, extracellular matrix; IL-5, interleukin-5; IL-5R, interleukin-5 receptor; PN, periostin; PSGL, P-selectin glycoprotein-1; VCAM, vascular cell adhesion molecule-1.